ES2219577T3 - SYNTHESIS OF ACID R (+) ALPHA-LIPOIC. - Google Patents

Abstract

Synthesis process of R (+) a-lipoic acid comprising the following steps: a) salification of racemic 6,8-halo-octanoic acid with S (-) ~ -methylbenzylamine, taking the molar ratio S (-) ~ methylbenzylamine / racemic 6,8-dihalo-octanoic acid a value between 0.45 and 0.65; b) filtration separation of the crystallized diastereoisomeric salt of S (-) - methylbenzylamine-R (+) - 6 acid, dihalo-octanoic acid; c) purification by recrystallization of the diastereoisomeric salt of S (-) - methylbenzylamine-R (+) - 6, 8-dihaoctanoic acid d) separation of the diastereoisomeric salt to obtain R (+) 6, 8-dihalo-octanoic acid by the reaction of said salt with strong mineral acids diluted in an aqueous solution, the dilution being between 2% and 10% by weight; e) esterification of R (+) 6,8-dihalo-octanoic acid to obtain the corresponding alkyl ester; f) reaction of the alkyl ester of R (+) 6,8-dihalo-octanoic acid in an organic solvent with an aqueous solution of alkali disulfide in the presence of a compound for phase transfer catalysis which has been selected from the group consisting of salts quaternary phosphonium or ammonium whose general formula is: ** (formula) ** where: A is nitrogen or phosphorus, X is selected from the group consisting of CI, Br, I, HSO4 and H2PO4, and the substituents R1, R2, R3 and R4 are selected from the group consisting of linear or branched alkyl radicals that include one to twenty carbon atoms (C1-C20), said substituents being identical or distinct from each other, or only one of said substituents being selected from the group consisting of arylalkyl radicals of formula (CH2) nC6H5 with n = 1-16; g) hydrolysis of the ester of R (+) a-lipoic acid.

Description

Acid synthesis R (+) α-lipoic.

The present invention relates to a process of synthesis of R (+) α-lipoic acid through formation of diastereoisomeric acid salts 6,8-racemic dihalooctanoic acid optic isomers of a-methylbenzylamine, acid separation R (+) - dihalooctanoic acid and its transformation into acid corresponding α-lipoic by catalysis of phase transfer

State of the art

The mixing resolution procedure racemic or racemate, that is, the decomposition of a racemate  in the enantiomers that constitute it, it is a good procedure known in the prior art. The racemate becomes first  place in a mixture of diastereoisomers by a reaction with an optically active substance. The diastereoisomers as well obtained, which are characterized by various physical properties among which is its solubility, they are generally separated by fractional crystallization. The enantiomers of the mixture Initial racemic are obtained from said separate diastereoisomers by means of simple chemical reactions of separation of said diestereoisomers.

In U.S. Patent 5,281,722 salts are described diastereoisomers that have been obtained from pure enantiomers of α-lipoic acid undergoing a reaction with optical isomers of α-methylbenzylamine. The known procedures describe methods for preparing said diastereoisomeric salts and their use as intermediates in the resolution of a racemic mixture of thioctic acid in both R (+) and S (-) optically active enantiomer forms of the acid α-lipoic. The resolution procedure of a racemic thioctic acid is low yield in the case particular of the separation of enantiomers R (+) α-lipoic (see examples 7 and 8 of U.S. Patent 5,281,722).

In fact, the purification procedures of diastereoisomeric salts described in the prior art have a low enantiomeric enrichment of the isomer salt R (+) α-lipoic.

This is also confirmed by the numerous recrystallizations to which salts are subjected diastereoisomerics before the cleavage reaction with acids

The tests carried out by the applicant demonstrate that the cleavage of purified diastereoisomeric salts by the addition of inorganic acids, such as, for example, mineral acids such as 1 N hydrochloric acid, to obtain the two forms of optically active enantiomers R (+) and S ( -) α-lipioco acid, according to the procedure described in US Patent 5,281,722, provides enantiomers of low-quality α-lipoic acid (presence of
polymers).

The prior art describes the use of salts. diastereoisomers obtained from acid enantiomers α-lipoic by a reaction with bases optically active to separate the R (+) and S (-) acid isomers α-lipoic. But according to the verifications performed by the applicant, the procedures described in the prior art are characterized by involving procedures long and complex to purify diestereoisomeric salts intermediate, obtaining a low performance in the resolution of racemates, the quality of the optical isomers being like this  Obtained unsatisfactory.

There was therefore a demand for a Synthesis procedure of the optical isomer R (+) of acid α-lipoic constituting an alternative to prior art procedures that include acid racemic thioctic as a reaction intermediate, and, in in particular, the demand for synthesis procedures that provided high performance optical acid isomers α-lipoic of high quality and purity.

Summary

A new procedure has now been found synthesis of R (+) α-lipoic acid by means of racemic acid resolution 6,8-dihalo-octanoic with base (S) -? -Methylbenzylamine optically active and its reaction by transfer catalysis of phase with the alkaline disulfide of the esterified enantiomer of the alkali-R (+) 6,8-dihalo-octonoate corresponding, overcoming said procedure the disadvantages characteristics of prior art procedures, such as the complexity, the low performance and the low quality of the optical isomers obtained.

The applicant found quite unexpected and surprisingly a new acid synthesis procedure R (+) α-lipoic by salification of 6,8-dihalo-octanoic acid with the optically active base of S (-) α-methylbenzylalin to obtain the salt diastereoisometric of S (-) α-methylbenzylamine acid (+) - 6,8-dihalo-octanoic, followed by fractional crystallization purification and excision of the salt with acids, thus obtaining the enantiomer (+) of 6,8-dihalooctanoic acid, which, once esterified, undergoes a catalysis reaction of phase transfer with aqueous disulfide solutions alkalines to obtain R (+) α-lipoic acid esterified

Detailed description of the invention

An objective of the present invention is to  both in an acid synthesis procedure R (+) α-lipoicium comprising the following stages:

a) acid salification Racemic 6,8-halo-octanoic with S (-) α-methylbenzylamine, taking the ratio molar S (-) α-methylbenzylamine / acid Racemic 6,8-dihalo-octanoic one value between 0.45 and 0.65;

b) salt separation by filtration crystallized diastereoisomer of S (-) α-methylbenzylamine acid R (+) 6,8-dihalo-octanoic;

c) salt recrystallization purification diastereoisomeric of S (-) α-methylbenzylamine acid R (+) - 6,8-dihalo-octanoic;

d) separation of the diastereoisomeric salt to get acid R (+) 6,8-dihalo-octanoic by reaction of said salt with strong mineral acids diluted in a aqueous solution, the dilution being between 2% and 10% by weight;

e) acid esterification R (+) 6,8-dihalo-octanoic for obtain the corresponding alkyl ester;

f) reaction of the acid alkyl ester R (+) 6,8-dihalo-octanoic in a organic solvent with an aqueous solution of alkaline disulfide in presence of a compound for transfer catalysis of phase that has been selected from the group formed by salts quaternary phosphonium or ammonium whose general formula is:

one

where:

A is nitrogen or phosphorus,

X is selected from the group consisting of CI, Br, I,

HSO 4 and H 2 PO 4, and the substituents R 1, R 2, R 3 and R 4 are selected from the group formed by linear or branched alkyl radicals that include one to twenty carbon atoms (C_ {1} -C_ {20}), being able to be said identical or different substituents, or by selecting only one of said substituents of the group consisting of radicals of arylalkyl of formula (CH 2) n C 6 H 5 with n = 1-16;

g) acid ester hydrolysis R (+) α-lipoic.

Halogenated Acid Substituents Racemic 6,8-dihalo-octanoic, which they can be identical or different from each other, they are selected from the group formed by CI, Br and I.

Said acid Racemic 6,8-dihalo-octanoic preferably consists of acid 6,8-dichlorooctanoic acid, which is a product that can easily acquired in the market and produced according to the description included in J.A.C.S., volume 79, 1957, pages 6483-6487.

According to the synthesis procedure described in the  present invention, the molar ratio S (-) α-methylbenzylamine / acid Racemic 6,8-dihalo-octanoic in the salification stage a) preferably takes a value between 0.48 and 0.60 and more preferably one between 0.50 and 0.58. The stage of salification a) is carried out at atmospheric pressure and in a solvent organic, which preferably consists of ethyl acetate, and at a temperature between 20 and 40 ° C, preferably the temperature between 25 and 30 ° C. Acid concentration Racemic 6,8-dihalo-octanoic in the salification stage a) is 10 to 40% w / v, preferably 15 at 35% w / v, and more preferably 20 to 30% w / v solvent.

Stage b), that is, the separation stage by  filtration of the diasteriomeric salt is carried out at a temperature between 0 and 10 ° C and preferably at 2 ° C.

In stage c), that is, in the stage of purification by recrystallization of the diastereoisomeric salt of S (-) α-methylbenzylamine acid R (+) 6,8-dihalo-octanoic, the Solvents used consist of alkyl esters of acids aliphatic or aromatic carboxylic acids, in which the alkyl is C 1 -C 3, and preferably in esters alkyl of aliphatic carboxylic acids with 2 to 4 atoms of carbon, said stage being carried out at a temperature between 40 and 65 ° C, although preferably between 45 and 60 ° C and more preferably between 50 and 55 ° C.

In stage d), that is, in the stage of separation of diastereoisomeric salt, aqueous mineral acid preferably consists of dilute sulfuric acid, the dilution of between 4 and 8% by weight and more preferably 5% in weight.

Stage e), that is, acid esterification  R (+) 6,8-dihalo-octanoic, comprises an esterification reaction according to well known procedures in the field of esterification of aliphatic carboxylic acids with aliphatic or aromatic alcohols.

According to the present invention, esters acid alkyl R (+) 6,8-dihalo-octanoic consist in linear or branched C 1 -C 6 esters, preferably in linear C 1 -C 3 esters or branched, and more preferably in methyl ester or ester ethyl.

According to the present invention, the amount of alkyl acid esters R (+) 6,8-dihalo-octanoic in the reaction of step f) is between 5 and 60% by weight, preferably between 10 and 40% by weight, and more preferably between 15 and 30% by weight with respect to the organic solvent.

The organic solvent used in the reaction of step f) consists of a solvent that cannot be mixed with water and that is selected from the group consisting of hydrocarbons C5 {C} -C10 {aliphatic, linear or branched, or C 5 -C 10 hydrocarbons aromatics also comprising substituent groups selected from the group consisting of nitro, nitrite or halogen, esters of aliphatic or aromatic carboxylic acids; linear or cyclic esters; Ketones C4 {C} {C10} linear or cyclic; disulfides of carbon; carbon tetrachlorides The solvent consists preferably in benzene or toluene.

The acid synthesis procedure R (+) α-lipoic according to the present invention comprises the phase transfer of the disulfide ion of the aqueous solution, which contains the alkali disulfide corresponding to the organic phase, which cannot be mixed with water  and contains the alkyl acidic ester R (+) 6,8-dihalo-octanoic. The aqueous solution of alkali disulfide can be prepared by subjecting sulfur (S) to a reaction in water with alkali sulphide correspondent.

Preferred alkali disulfides are the sodium disulfide (Na2S2) and potassium disulfide (K 2 S 2) or a mixture of both, with the most preferred being sodium disulfide

In the reaction of step f) of the procedure of synthesis of R (+) α-lipoic acid according to the present invention, the alkali disulfide / ester molar ratio acid alkyl R (+) 6,8-dihalo-octanoic takes a value between 0.8 and 1.2, preferably between 0.9 and 1.1, and with more Preference between 0.95 and 1.0.

Preferred compounds for catalysis of phase transfer, which are used in acid synthesis R (+) α-lipoic object of the present invention, are selected from the group consisting of bromide of tetrabutylammonium, tetrabutylphosphonium bromide, chloride methyltrioctylammonium (ALIQUAT (R) 336), chloride methyl- (C 8 -C 10) - trialkylammonium (ADOGEN (R) 464) and tetrabutylammonium hydrogen sulfate; and more preferably they are tetrabutylammonium bromide and hydrogen sulfate of tetrabutylammonium.

According to the synthesis procedure described in the  present invention, the compound for transfer catalysis phase, which participates in the reaction of stage f) and consists of a quaternary salt, is in an amount between 0.5 and 10% in moles, preferably between 1 and 5% in moles, and with more preference between 2 and 4 mol% with respect to the alkyl ester of 6,8-dihalo-octanoic acid.

The reaction temperature of step f) is it is between 20 and 130ºC, preferably between 60 and 100ºC, and with more preference between 80 and 90 ° C.

Step g), that is, the hydrolysis of the ester of R (+) α-lipoic acid, consists of a hydrolysis with alkali hydroxides / alkaline earth in presence of organic solvents, such as alcohols and polyols, esters and hydroxy esters, ketones and hydroxyketones, which can mix with water in a volume ratio of 50:50 to 95: 5 and to a temperature between 0 and 100 ° C. The concentration of the ester with regarding the organic solvent is between 5 and 50% w / v and the ratio molar ester / hydroxide takes a value between 0.5 and 1. It can be recover free R (+) α-lipoic acid by a treatment with aqueous mineral acids, being the dilution of between 1 and 20% by weight, or by acid treatment Water soluble organic.

The reaction products and products intermediates are characterized by analysis of 1 H-NMR, mass and HPLC.

Below are some examples to title of illustration, understanding that they do not limit the scope of the  present invention

Example 1

a) 40g (0.187 moles) of acid are dissolved 6,8-racemic dichlorooctanoic acid in 150 ml of ethyl acetate at 25-30 ° C. To this solution are added then 12.3 g (0.101 mol) of S (-) -? -Methylbenzylamine. I know first cool said solution to 18-20 ° C, until precipitation begins to occur, and then to 0-5ºC. The solid thus obtained is filtered and proceed to wash it with ethyl acetate (10 ml) to obtain 15.3 g of wet salt of S (-)? -methylbenzylamine-acid (+) - 6,8-dichlorooctanoic.

b) The mother liquors obtained with the crystallization that occurs in stage a) are extracted with 100 ml of 5% sulfuric acid by weight, verifying that the pH of the aqueous phase takes a value equal to 1. It is washed twice the organic phase with 20 ml of water and then proceed to concentrate by distilling the solvent at atmospheric pressure until reaching a volume of 130-140m1. 9.75 g (0.08 mol) of R (+)? -Methylbenzylamine are added to the solution and it is cooled first to 18-20 ° C, until precipitation begins to occur, and then to
0-5 ° C The solid is filtered and washed with 10 ml of ethyl acetate, thus obtaining 8.2 g of wet salt of R (+)? -Methylbenzylamine-acid (-) - 6,8-dichloroctanoic acid.

c) The mother liquors obtained with the crystallization that occurs in stage b) is extracted with 50 ml of 5% sulfuric acid by weight, verifying that the pH of the aqueous phase takes a value ≤1. The phase is washed twice organic with 20 ml of water and then proceed to concentrate it by distilling the solvent at atmospheric pressure until reach a volume of 40-45 ml. They are added to the 50 ml solution of ethyl acetate and 9.8 g (0.081 mol) of S (-)? -Methylbenzylamine and proceed to cool first to 18-20 ° C, until it starts to precipitation occurs, and then to 0-5ºC. The solid is filtered and washed with 10 ml of ethyl acetate, thus obtaining 12 g of wet salt from S (-) α-methylbenzylamine acid (+) - 6,8-dichlorooctanoic.

d) The wet salts of S (-) α-methylbenzylamine acid (+) - 6,8-dichlorooctanoic obtained in stages a) and c) and crystallize twice using each time 55 ml of ethyl acetate. 16 g of wet product are obtained which dried under vacuum, thus obtaining 13.5 g of the salt of S (-) α-methylbenzylamine acid (+) - 6,8-dichlorooctanoic. I know suspend said salt in a mixture of water (60 ml) and toluene (60 ml) and proceed to acidify it with 5% sulfuric acid by weight until reach a pH 1. 1. The organic phase is separated and proceed to concentrate in vacuo, thus obtaining 9 g of acid (+) - 6,8-dichlorooctanoic (45% yield).

[α] 24 D = 26.7 (c = 2, ethanol)

Example 2

9 g (0.042 mol) of acid are dissolved (+) - 6,8-dichlorooctanoic acid in 120 ml of methanol containing 0.45 ml of 37% hydrochloric acid in weight. The solution is heated at reflux for two hours, evaporate the solvent under reduced pressure, 17 ml of toluene are added and the solution is washed twice with 10 ml of water obtained. The toluene phase is then concentrated in vacuo, thus obtaining 9.4 g of methyl (+) - 6,8-dichlorooctanoate (98.6% yield).

[α] 20 D = 26.5 (c = 1, toluene)

Example 3

It is heated at 85 ° C and for 30 minutes a mixture of 5.65 g (0.043 mol) of 60% by weight sodium sulfide, 1.18 g (0.037 mol) of sulfide and 20 ml of water. After filtering the mixture to extract the non-soluble part, is added for three hours the solution obtained to a solution formed by 9.4 g (0.041 moles) of methyl (+) - 6,8-dichlorooctanoate, 0.37 g (0.0011 mol) of tetrabutylammonium bromide and 18.5 ml of toluene, keeping the solution at 82 ° C. The mixture is heated to reflux (90 ° C) for 1 hour and then cooled to 30 ° C. The organic phase is separated and washed with 5 ml of water. Then, everything is concentrated under vacuum, thus obtaining 8.6 g of R (+) α-lipoic acid methyl ester (94.4% yield).

The final product is characterized by 1 H-NMR and mass analysis:

-

1 H-NMR - δ (300 MHz, CDCI3): 1.4 (2H, m); 1.67 (4H, m); 1.83 (1 H, td); 2.24 (2H, t); 2.4 (1 H, td); 3.1 (2H, m); 3.5 (1 H, m); 3.66 (3H, s).

-

Mass (El): 220 (M +); 189 (-CH 3 O)

[α] 20 D = 88 (c = 1.8 toluene)

Example 4

8.6 g (0.039 mol) of methyl ester are added of the R (+) α-lipoic acid to a solution that consists of 2.36 g (0.042 moles) of 95% potassium hydroxide in weight, 19 ml of methanol and 3.8 ml of water. The mixture is heated obtained for two hours at 50 ° C, it is cooled to 30 ° C and 40 ml of toluene are then added. Everything is acidified with 10% phosphoric acid by weight, maintaining the temperature by below 30 ° C. The organic phase is separated and the wash it three times using 10 ml of an aqueous solution each time of 10% by weight sodium chloride. The solution is dehydrated on sodium sulfate and proceed to concentrate until dry evaporating the solvent in vacuo. 3.3 ml of ethyl acetate are added and 41 ml of cyclohexane, the solution is heated to 40 ° C, proceed to treat it with decolorizing carbon and slowly cool the solution clear thus obtained until reaching 0 ° C. The material is filtered solid and proceed to wash it with 5 ml of cyclohexane, obtaining thus 3.6 g of R (+) α-lipoic acid (45% yield).

[α] 20 D = 119.1 (c = 1, ethanol)

e.e> 99% (HPLC).

Claims (31)

1. Acid synthesis procedure R (+) α-lipoic comprising the following stages: a) acid salification Racemic 6,8-halo-octanoic with S (-) α-methylbenzylamine, taking the ratio molar S (-) α-methylbenzylamine / acid Racemic 6,8-dihalo-octanoic one value between 0.45 and 0.65; b) salt separation by filtration crystallized diastereoisomer of S (-) α-methylbenzylamine acid R (+) - 6,8-dihalo-octanoic; c) salt recrystallization purification diastereoisomeric of S (-) α-methylbenzylamine acid R (+) - 6,8-dihalo-octanoic d) separation of the diastereoisomeric salt to get acid R (+) 6,8-dihalo-octanoic by reaction of said salt with strong mineral acids diluted in a aqueous solution, the dilution being between 2% and 10% by weight; e) acid esterification R (+) 6,8-dihalo-octanoic for obtain the corresponding alkyl ester; f) reaction of the acid alkyl ester R (+) 6,8-dihalo-octanoic in a organic solvent with an aqueous solution of alkaline disulfide in presence of a compound for transfer catalysis of phase that has been selected from the group formed by salts quaternary phosphonium or ammonium whose general formula is: two where: A is nitrogen or phosphorus, X is selected from the group consisting of CI, Br, I, HSO 4 and H 2 PO 4, and the substituents R 1, R 2, R 3 and R 4 are selected from the group formed by linear or branched alkyl radicals that include from one to twenty carbon atoms (C_ {1} -C_ {20}), being able to be said identical or different substituents, or by selecting only one of said substituents of the group consisting of radicals of arylalkyl of formula (CH 2) n C 6 H 5 with n = 1-16; g) acid ester hydrolysis R (+) α-lipoic. 2. Method according to claim 1, in the  that said halogenated acid substituents Racemic 6,8-dihalo-octanoic, which they can be identical or differ from each other, they are selected from the group formed by CI, Br and I. 3. Method according to claim 2, in the  that 6,8-dihalo-octanoic acid Racemic is 6,8-dichlorooctanoic acid. 4. Method according to claim 1, in the  that the molar relationship S (-) α-methylbenzylamine / acid Racemic 6,8-dihalo-octanoic acid salification stage a) takes a value between 0.48 and 0.60. 5. Method according to claim 4, in the  that the molar relationship S (-) α-methylbenzylamine / acid Racemic 6,8-dihalo-octanoic takes a value between 0.5 and 0.58. 6. Method according to claim 1, in the  that acid concentration Racemic 6,8-dihalo-octanoic used in the salification stage a) takes a value between 10 and 40% w / v solvent. 7. Method according to claim 6, in the  that acid concentration Racemic 6,8-dihalo-octanoic takes a value between 15 and 35% w / v of solvent. 8. Method according to claim 7, in the  that acid concentration Racemic 6,8-dihalo-octanoic takes a value between 20 and 30% w / v of solvent. 9. Method according to claim 1, in the  that the aqueous mineral acid used in step d), that is, in The step of separating the diastereoisometric salt consists of diluted sulfuric acid, the dilution being between 4 and 8% in weight. 10. Method according to claim 9, in which sulfuric acid is diluted to 5% by weight. 11. Method according to claim 1, in which said alkyl acid esters R (+) 6,8-dihalo-octanoic consist in linear C 1 -C 8 esters or branched. 12. Method according to claim 11, in which said alkyl acid esters R (+) 6,8-dihalo-octanoic consist in linear C 1 -C 3 esters or branched. 13. Method according to claim 12, in which said alkyl acid esters R (+) 6,8-dihalo-octanoic consist in methyl ester or ethyl ester. 14. Method according to claim 1, in which the amount of alkyl acid esters R (+) 6,8-dihalo-octanoic which involved in the reaction of stage f) is between 5 and 60% in weight with respect to organic solvent. 15. Method according to claim 14, in which the amount of alkyl acid esters R (+) 6,8-dihalo-octanoic is from between 10 and 40% by weight with respect to the organic solvent. 16. Method according to claim 15, in which the amount of alkyl acid esters R (+) 6,8-dihalo-octanoic is from between 15 and 30% by weight with respect to the organic solvent. 17. Method according to claim 1, in that the organic solvent used in the reaction of step f) it consists of a solvent that cannot be mixed with water and that select from the group consisting of aliphatic hydrocarbons C_ {5} -C_ {10} linear or branched, or by C 5 -C 10 aromatic hydrocarbons that they also include substituent groups selected from the group formed by nitro, nitrile or halogen groups, acid esters aliphatic or aromatic carboxylic; linear or cyclic esters; C4 {C} {10} linear or cyclic ketones; carbon disulfides; carbon tetrachlorides 18. Method according to claim 17, in which said solvent is benzene or toluene. 19. Method according to claim 1, in which alkali disulfides consist of sodium disulfide (Na 2 S 2) or potassium disulfide (K 2 S 2) or a mix of both. 20. Method according to claim 19, in which said alkaline disulfide is sodium disulfide. 21. Method according to claim 1, in which the alkali disulfide / alkyl ester molar ratio of R (+) 6,8-dihalo-octanoic acid considered in the reaction of step f) takes a value between 0.8 and 1,2. 22. Method according to claim 21, in which said molar ratio takes a value between 0.9 and 1.1. 23. Method according to claim 22, in which said molar ratio takes a value between 0.95 and 1.0. 24. Method according to claim 1, in the I that quaternary ammonium or phosphonium salts are selected from the group consisting of tetrabutylammonium bromide, tetrabutylphosphonium, methyltrioctylammonium chloride (ALIQUAT (R)) 336), chloride methyl- (C 8 -C 10) - trialkylammonium (ADOGEN (R) 464) and tetrabutylammonium hydrogen sulfate. 25. Method according to claim 24, in which said quaternary salts are tetrabutylammonium bromide or tetrabutylammonium hydrogen sulfate. 26. Method according to claim 1, in the amount of quaternary ammonium or phosphonium salts is between 0.5 to 10 mol% with respect to the alkyl ester of the acid 6,8-dihalo-octanoic. 27. Method according to claim 26, in which the amount of said quaternary salt is between 1 and 5% in moles with respect to the alkyl ester of the acid 6,8-dihalo-octanoic. 28. Method according to claim 27, in which the amount of said quaternary salt is between 2 and 4% in moles with respect to the alkyl ester of the acid 6,8-dihalo-octanoic. 29. Method according to claim 1, in the temperature at which the stage reaction occurs f) is between 20 and 130 ° C. 30. Method according to claim 29, in which said temperature is between 60 and 100 ° C. 31. Method according to claim 30, in which said temperature is between 80 and 90 ° C.